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The Journal of Neuroscience, April 21, 2004, 24(16):3899-3906; doi:10.1523/JNEUROSCI.0283-04.2004

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Neurobiology of Disease
Age-Dependent Neurodegeneration and Alzheimer-Amyloid Plaque Formation in Transgenic Drosophila

Isabell Greeve,^1,2 Doris Kretzschmar,³ Jakob-Andreas Tschäpe,³ Anika Beyn,^1,5 Claire Brellinger,¹ Michaela Schweizer,¹ Roger M. Nitsch,^1,4 and Rita Reifegerste^1,5

¹Center for Molecular Neurobiology, University of Hamburg, 20251 Hamburg, Germany, ²Department of Neurology, Inselspital University Hospital Bern, 3010 Bern, Switzerland, ³Center for Research on Occupational and Environmental Toxicology, Oregon Health and Sciences University, Portland, Oregon 97201, ⁴Division of Psychiatry Research, University of Zurich, 8008 Zurich, Switzerland, and ⁵Evotec Neurosciences GmbH, 22525 Hamburg, Germany

-Amyloid peptides that are cleaved from the amyloid precursor protein (APP) play a critical role in Alzheimer's disease (AD) pathophysiology. Here, we show that in Drosophila, the targeted expression of the key genes of AD, APP, the-site APP-cleaving enzyme BACE, and the presenilins led to the generation of -amyloid plaques and age-dependent neurodegeneration as well as to semilethality, a shortened life span, and defects in wing vein development. Genetic manipulations or pharmacological treatments with secretase inhibitors influenced the activity of the APP-processing proteases and modulated the severity of the phenotypes. This invertebrate model of amyloid plaque pathology demonstrates A-induced neurodegeneration as a basic biological principle and may allow additional genetic analyses of the underlying molecular pathways.

Key words: Alzheimer; dementia; aging; neuropathology; degeneration; Drosophila

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Received Jan 25, 2004; revised March 7, 2004; accepted March 8, 2004.

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